Synthesis and biological activity of 2-aminothiazoles as novel inhibitors of PGE2 production in cells

被引：47

作者：

Smith, Breland ^{[1
,2
]}

Chang, Hui-Hua ^{[3
,4
]}

Medda, Federico ^{[1
]}

Gokhale, Vijay ^{[5
]}

Dietrich, Justin ^{[1
]}

Davis, Angela ^{[5
]}

Meuillet, Emmanuelle J. ^{[3
,4
]}

Hulme, Christopher ^{[1
,5
]}

机构：

[1] Univ Arizona, Oro Valley BIO5, Oro Valley, AZ 85737 USA

[2] Univ Arizona, Dept Chem & Biochem, Tucson, AZ 85721 USA

[3] Univ Arizona, Dept Nutr Sci, Arizona Canc Ctr, Tucson, AZ 85724 USA

[4] Univ Arizona, Dept Mol & Cellular Biol, Arizona Canc Ctr, Tucson, AZ 85724 USA

[5] Univ Arizona, Dept Pharmacol & Toxicol, Coll Pharm, Tucson, AZ 85721 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 10期

关键词：

2-Aminothiazoles; PGE(2); Colon cancer; COX-2; MPGES-1; HALLMARKS;

D O I：

10.1016/j.bmcl.2012.03.013

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

This Letter presents the synthesis and biological evaluation of a collection of 2-aminothiazoles as a novel class of compounds with the capability to reduce the production of PGE(2) in HCA-7 human adenocarcinoma cells. A total of 36 analogs were synthesized and assayed for PGE(2) reduction, and those with potent cellular activity were counter screened for inhibitory activity against COX-2 in a cell free assay. In general, analogs bearing a 4-phenoxyphenyl substituent in the R-2 position were highly active in cells while maintaining negligible COX-2 inhibition. Specifically, compound 5l (R-1 = Me, R-2 = 4-OPh-Ph, R-3 = CH(OH)Me) exhibited the most potent cellular PGE(2) reducing activity of the entire series (EC50 = 90 nM) with an IC50 value for COX-2 inhibition of >5 mu M in vitro. Furthermore, the anti-tumor activity of analog 1a was analyzed in xenograft mouse models exhibiting promising anti-cancer activity. (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：3567 / 3570

页数：4

共 17 条

[1] Nonsteroidal Anti-Inflammatory Drugs: A Critical Review on Current Concepts Applied to Reduce Gastrointestinal Toxicity [J].

Abdel-Tawab, Mona ;

Zettl, Heiko ;

Schubert-Zsilavecz, Manfred .

CURRENT MEDICINAL CHEMISTRY, 2009, 16 (16) :2042-2063

[2]

[Anonymous], COX 2 CELL FREE ASS

[3]

Chang H.H., J INVEST NEW DRUGS

[4] Substituted phenanthrene imidazoles as potent, selective, and orally active mPGES-1 inhibitors [J].

Cote, Bernard ;

Boulet, Louise ;

Brideau, Christine ;

Claveau, David ;

Ethier, Diane ;

Frenette, Richard ;

Gagnon, Marc ;

Giroux, Andre ;

Guay, Jocelyne ;

Guiral, Sebastien ;

Mancini, Joseph ;

Martins, Evelyn ;

Masse, Frederic ;

Methot, Nathalie ;

Riendeau, Denis ;

Rubin, Joel ;

Xu, Daigen ;

Yu, Hongping ;

Ducharme, Yves ;

Friesen, Richard W. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2007, 17 (24) :6816-6820

[5] Microsomal prostaglandin E2 synthase-1 (mPGES-1):: A novel anti-inflammatory therapeutic target [J].

Friesen, Richard W. ;

Mancini, Joseph A. .

JOURNAL OF MEDICINAL CHEMISTRY, 2008, 51 (14) :4059-4067

[6] Discovery of disubstituted phenanthrene imidazoles as potent, selective and orally active mPGES-1 inhibitors [J].

Giroux, Andre ;

Boulet, Louise ;

Brideau, Christine ;

Chau, Anh ;

Claveau, David ;

Cote, Bernard ;

Ethier, Diane ;

Frenette, Richard ;

Gagnon, Marc ;

Guay, Jocelyne ;

Guiral, Sebastien ;

Mancini, Joseph ;

Martins, Evelyn ;

Masse, Frederic ;

Methot, Nathalie ;

Riendeau, Denis ;

Rubin, Joel ;

Xu, Daigen ;

Yu, Hongping ;

Ducharme, Yves ;

Friesen, Richard W. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2009, 19 (20) :5837-5841

[7] The COX-2/PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment [J].

Greenhough, Alexander ;

Smartt, Helena J. M. ;

Moore, Amy E. ;

Roberts, Heather R. ;

Williams, Ann C. ;

Paraskeva, Christos ;

Kaidi, Abderrahmane .

CARCINOGENESIS, 2009, 30 (03) :377-386

[8] Novel human mPGES-1 inhibitors identified through structure-based virtual screening [J].

Hamza, Adel ;

Zhao, Xinyun ;

Tong, Min ;

Tai, Hsin-Hsiung ;

Zhan, Chang-Guo .

BIOORGANIC & MEDICINAL CHEMISTRY, 2011, 19 (20) :6077-6086

[9] The hallmarks of cancer [J].

Hanahan, D ;

Weinberg, RA .

CELL, 2000, 100 (01) :57-70

[10] Hallmarks of Cancer: The Next Generation [J].

Hanahan, Douglas ;

Weinberg, Robert A. .

CELL, 2011, 144 (05) :646-674

← 1 2 →